Pancreatic cancer has the highest death to incidence ratio (approximately 0.99) of all cancers. Survival time for pancreatic cancer patients is measured in months, rather than years, where the mean survival time is 3-6 months from the time of diagnosis. The major reasons for this dismal prognosis come from the fact that pancreatic cancers disseminate at a high frequency and are resistant to traditional chemotherapeutics and radiation for reasons that are unclear. We find it striking that pancreatic carcinomas display cytoarchitecture that is reminiscent of morphologically differentiated cells, which by their nature are resistant to chemotherapies. We postulate that this observation may hold the key to the resistance of pancreatic cancers to treatment. The long- term goal of this project is to better understand the mechanisms governing the aggressive and drug-resistant nature of pancreatic carcinomas so that more effective treatments can be developed for pancreatic cancer. The objective of this proposal is to determine if upregulation of the pro-invasive integrin ?6?4, which is associated with apoptosis resistance and is highly expressed in pancreatic carcinomas, can contribute to the aggressive and resilient nature of pancreatic adenocarcinomas. The central hypothesis of this grant proposal is that the integrin ?6?4 and its ligands are upregulated early in tumor progression at high frequency and promote the chemotherapeutic resistance of pancreatic cancer cells by facilitating a unique three-dimensional architecture. Our first aim is to determine if the ?6?4 integrin can mediate resistance of pancreatic carcinoma cells to traditional chemotherapies. To study this phenomenon properly, we expect that the accurate modeling of the context of the cells will be critical and thus have developed a three-dimensional culture system for this purpose. In our second aim, we will define the stage at which integrin ?6?4 and its ligands are overexpressed and mislocalized in human pancreatic tumor progression. We are well positioned to undertake the proposed research since the principal investigator has a solid background in the biology of integrins in invasive carcinoma cells. We have the expertise and support of clinical scientists who are involved in the diagnosis and treatment of patients with pancreatic disease at UTMB. In addition, we have well-developed models for studying integrin ?6?4 in pancreatic cancer, which includes multiple pancreatic cell lines, immunohistochemical staining of archival tissues for integrin ?4 subunit, and three-dimensional cultures for studying the effects of cytoarchitecture. Ultimately, our studies are significant because they will contribute to the understanding of drug resistance in pancreatic cancer that, in time, will allow us to decrease the morbidity and mortality of pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: The poor prognosis for pancreatic cancer patients persists due to a high incidence of invasion and metastasis and a lack of effective treatment options due to the drug-resistant nature of pancreatic cancer cells. Based on our preliminary data and knowledge of the biology of integrins in advanced cancers, objective of this proposal is to determine if upregulation of the pro-invasive integrin ?6?4, which is highly expressed in pancreatic carcinomas, can contribute to the aggressive and apoptosis/drug-resistant nature of pancreatic carcinomas. Ultimately, our studies will be significant because they will contribute to the understanding of drug resistance in pancreatic cancer that, in time, will allow us to decrease the morbidity and mortality of pancreatic cancer patients through the development of more effective treatments. [unreadable] [unreadable] [unreadable]